The availability and utilization of macronutrients contribute to feeding regulation, as do several chemical systems within the brain. The proposed experiments will examine the relationship between one nutrient, glucose, and a group of neuromodulators, the opioid peptides. An interrelationship between the opioid system and circulating glucose levels is not without precedent. Since the 1950's it has been known that blood glucose concentration can affect the antinociceptive properties of opiates. Our laboratory has described an alteration in responsivity of animals to opioid-induced feeding due to the glycemic state of the organisms. It is the intent of the present grant to answer a variety of questions related to such a glucose-opioid interaction as it relates to the control of ingestive behaviors. In animals made diabetic by the administration of streptozotocin, we will use several agonists with different selectivities to determine which receptor is most affected, as reflected by responsivity to opioid-induction of feeding. We will also study, by ventricular injections and localized infusions into specific brain sites, the neural structures that are most likely involved in glucose modulation of opioid induced feeding. We will evaluate the effect of the glycemic state on the "reverse-tolerance" noted following repeated injection of various opiate agents. The next group of studies will attempt to achieve the same modulation of opioid effects through the use of glucose injections directly into various brain sites. We will conduct in vitro ligand-binding studies with isolated brain membranes using a variety of glucose concentrations in the incubation media. These binding studies will provide information both on the nature of opioid agonist-receptor binding and on the mechanism underlying the expected effects of diabetes on opioid-induced feeding. The results of these experiments should integrate two fields of appetite research: glucose and opioid-regulation. Diseases which involve compulsive eating may represent a type of self-addiction. The addictive characteristic may be due to relationships between nutrients (eg. glucose) and neuroregulators (eg. opioids). Thus, the agents involved and the specific control sites are necessary ingredients to the design of appropriate clinical treatment for such eating disorders. We believe that the results of our studies will be applicable at both the basic and the applied level.